2-oxo-1(2h)-pyridinecarbonitrile and substituted derivatives thereof

ABSTRACT

2-OXO-1(2H)-PYRIDINECARBONITRILE AND DERIVATIVES THEREOF HAVE ANTICANDIDAL ACTIVITY. THEY MAY ALSO BE REACTED   WITH A NUCLEOPHILE TO FORM A 2-PYRIDONE AND A CYANATED NUCLEOPHILE.

R s sm r R KM E 1... m ME M 9 N P m o 2 E r N cN 4 6 1 N nl TSG mmz s: n ML M Rw w Ss @s SQ N ML m L M w W DERIVATIVES THEREOF Flled May 28, 1971 W l. PARKER ETAL 2OXO1 (2H)-FYRIDINECARBONITRILE AND SUBSTITUTED Oct. 30, 1973 nucleophile.l

lUnited States Patent Office 3,769,291 Patented Oct. 30, 1973 v l l I 769.2916 ZeOXO-IQID-PYRIDINECARBONITRILE AND SUBSTITUTED DERIVATIVES THEREOF lWillialyn"LawrenceV Parker, North Brunswick, and Saul Lewis,NeidlemamfIrenton, NJ., assiguors to E. R. 1 Squibb & Sons, Inc., New York, NY.

-Continuation-in-part of abandoned application Ser. No.

111,125, Jan; 29, 19713.*This application May 28, 1971, SQNo. 148,037 3 AInt. Cl. C07d 31/42 f ABS'maarv or DISCLOSURE .y -oxo-1".(2VH)pyridinecarbonitrile and derivatives thereofihaveantic'andidal activity. Theyv` may also be reacted Qwyith' a, nucleophileto forml a"2ppyridone and a cyanated Candida, a genus]ofl yeast-like microorganisms, is responsiblefor-Alarious pathogenic conditions in humans. "andda'albcans,"for'example, isresponsible for thrush and othervutypesgof moniliasis.

ubstitted 2;pyri'dones are useful intert 2:pyrid0nea .Y mediates for various compounds, e.g. 2-chloropyridines.

"'Valios cyanamides are useful herbicides and are usevful intermediates for carb mates and guanidines.

sUivrr/IARYl olfrHE `INVENTION y Compounds of the vformula y v Y N .a EN (II) wherein each R may be the same or dierent and may be hydrogen, lower alkylor lower alkenyl of up to 12 carbon atoms, hydrorcyhlower alkoxy of up to l2 carbon atoms, nitro, cyano. halogen. .Carbono amidQmeICaPO. aliphati"j or aromatic acylfr'pdicals of up to 20 carbon atoms",v `plglenyl radicalsubstituted by one of the foregoingfsub'stituents,phenyl oraryloxy of up to 10r carbon "atoms, and wherein ,a l ,djac'e'ntll groups taken together may` be a phenyl i`n`g,"lave been found to` have.. anticandidal activity. These compounds may beprepared by reacting 2-acetoacetamido-pyridine or a derivative thereof with an alkali metalnitrite at an acidic pH, or by reacting a salt of 2(1 II)-pyridone, or a derivative thereof, withY a cyanogen halidefl'he reaction of a compound and acyanide;V "'51 DETAILED DESCRIPTION The compounds of the present invention may be prepared according to the following reaction sequence:

An acetoacetamidopyridine compound of Formula I is reacted with a nitrite salt at an acidic pH to form a 2-oxo-1(2E)-pyridinecarbonitrile compound of Formula II. The nitrite salt may be a water-soluble alkali metal nitrite, eg., LiNO2, NaNOZ, KNOZ, or a Water-soluble alkaline earth metal nitrite, e.g Ca (NO2) 2. The reaction takes place in aqueous medium at lowered temperatures, preferably at temperatures below about 10 C., and most preferably at about 0 C. The compound of Formula II is extracted from the aqueous medium by means of a water-immiscible organic solvent, such as an ester, eg., ethyl acetate; an ether, e.g. ethyl ether; a halogenated alkane, eg., chloroform; or an aromatic solvent, e.g., benzene, toluene or xylene.

The compound of Formula II may also be prepared by reacting an alkali metal salt of a 2-pyridone compound of Formula III with a cyanogen halide. This reaction takes place in a polar solvent at lowered temperatures. Suitable solvents are amides, e.g. dimethylformamide or dimethylacetamide; or ethers, e.g. bis(2methoxyethyl)ether. Suitable temperatures are from about 10 C. to about 10 C., preferably at about 0 C.

The alkali metal salt of the Z-pyridone compound of Formula III may be obtained-by reacting a compound of Formula III with an alkali metal hydroxide, c g. LiOH, NaOH, or KOH; an alkali metal hydride, e.g. LiI-I, NaH, or KH; an alkali metal amide, e.g. LiNH2, NaNHZ, or KNI-lz; or an alkyl organo-alkalimetal compound, e.g. Li-butyl, Nabutyl or K-butyl. l

The vcyan'ogen halide employed to convert the alkali metal salt, of the compound of Formula III to the correspondingcompound of Formula II is preferably cyanogen'bromide or cyanogen chloride.

lThe compounds of rFormula II maybe reacted with 'a nucleophilic compound. The nucleophilic compoundmay be any compoundfromy which an anion may be generated, `usually by means of a strong base. As typical nucleophilic compounds there may be mentioned lalcohol, thiols, airlines, ammonia, phenols,'thiophen`ols, Grignard reagents and malonic esters. Thus, the nucleophilic compound may have the formula QM wherein Q may be alkyl, alkoxy, thioalkyl, aryl, aryloxy, arylthio, amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, or a basic nitrogen containing heterocyclic radical attached to M through the nitrogen atom, and wherein M may be H, alkali metal, alkaline earth metal, Tl, divalent Cd, MgBr, MgQ or CaQ. Reaction of a compound of Formula II with a nucleophile of formula QM forms a Z-pyridone of Formula IV and, correspondingly, a cyanide of formula QCN. When the nucleophile is ammonia, the cyanated product is cyanamide.

Specific examples of such nucleophiles are following:

(I) Alcohols containing from 1 to 20 carbon atoms.

(A) Primary alcohols such as alkanols, cycloalkanols, and aryl-substituted alkanols, e.g., methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, n-dodecanol, ntetradecanol, n-hexadecanol, n-octadecanol, Z-methyl-lpropanol, isoamylalcohol, 2-methyl-1-butanol, benzyl alcohol, cyclohexylcarbinol, ethylene glycol and trimethylene glycol.

(B) Secondary alcohols, such as alkanols, cycloalkanols Iand aryl-substituted alkanols, e.g., 2-propanol, 2- methyl-Z-propanol, 3-methyl-2-butanol, 2-pentanol, 3- pentanol, 3-hexano1, benzhydrol, cyclohexanol and dicyclohexylcarbinol.

(C) Tertiary alcohols, such as alkanols, cycloalkanols and aryl-substituted alkanols, e.g., t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol, triphenylcarbinol and tricyclohexylcarbinol.

(D) Mixed alcohols having primary and secondary alcohol groups, e.g., propylene glycol, glycerol, lf2-methylglycerol, glucose, fructose, apiose, mannose, mannitol, galactose and acrose.

(II) Thiols containing from 1 to 20 carbon atoms corresponding to the foregoing alcohols. The thiols, or mercaptans, are prepared conveniently by heating alkyl halides with sodium hydrosulide.

(III) Ammonia and organic amines containing from 1 to 20 carbon atoms, and alkali and alkaline earth metal derivatives thereof.

(A) Primary alkylamines, cycloalkylamines, aryl-substituted alkylamines, and aromatic amines, e.g., methylamine, ethylamine, n-propylamine, isopropylamine, nbutylamine, isobutylamine, t-butylamine, n-amylamine, n-hexylamine, n-octylamine, 2-aminooctane, 2-ethyl-1- aminohexane, n-decylamine, laurylamine, cyclohexylamine, benzylamine, a-phenylethylamine, IB-phenylethylamine, aniline, and amnopyridine.

(B) Secondary amines such as dialkylamines, aryl-substituted alkylamines, dicyclohexylamines and diarylamines, and N-heterocyclic amines, e.g., dimethylamine, diethylamine, di n propylamine, diisopropylamine, ethyl-sec-butylamine, diphenylamine, benzylaniline, N- methylaniline, N-ethylaniline, N-phenylbenzylamine, N- methylbenzylamine, diphenylamine, dicyclohexylamine, morpholine, piperidine, pyrrolidine, pyrrole, pyrrolidine, pyrazole, imidazole, benzopyrrole, skatole, 2-methylindole, 2-phenylindole, 1,2,3,4-tetrahydroquinoline, decahydroquinoline and carbazole.

(IV) Phenols such as phenol and substituted phenols containing from 6 to 12 carbon atoms, such as o-cresol, m-cresol, p-cresol, o-chlorophenol, m-chlorophenol, pchlorophenol, p-bromophenol, 2,4,6-trichlorophenol, 2,4,6- trifluorophenol, o-nitrophenol, m-nitrophenol, p-nitrophenol, 2,4-dinitrophenol, guaiacol, saligenin, carvacrol, thymol, o-hydroxydiphenyl, p-hydroxydiphenyl, o-cyclohexylphenol, p-cyclohexylphenol, catechol, resorcinol, hydroquinone, pyrogallol and phloroglucinol.

(V) Thiophenols include thiophenol and substituted thiophenols containing from 6 to 12 carbon atoms corresponding to the foregoing Phenols,

(VI) Grignard reagents of the formula RMgX wherein R is an organic radical which forms a Grignard reagent and X is halogen, e.g., R may be alkyl, cycloalkyl, aryl, substituted alkyl, substituted cycloalkyl or substituted aryl.

(VII) Malonic esters, e.g., Na+ [CH(COOC2H5)2] i (VIII) Organometallic compounds wherein the organic radical may be alkyl or aryl and the metal may be an alkali metal or an alkaline earth metal or divalent Cd, e.g., butyl Li, phenyl Li, ethyl Na, amyl Na, octyl Na, diphenyl Mg, diethyl Mg, diethyl Ca, and dioctyl Cd.

The reaction between the compound of Formula II and the nucleophile of formula QM takes place in the presence of easily volatilized inert solvents, that is, solvents which have a boiling point not over about 100 C. at atmospheric pressure. The choice of solvents depends essentially upon the solubilities of the reactants. The reaction may take place at temperatures in the range of about 0 C. to about the boiling point of the solvent, preferably at about room temperature. As examples of suitable solvents, there may be mentioned ethers, e.g., ethyl ether or dioxane, aromatic solvents, e.g., benzene, toluene or xylene, halogenated solvents, e.g., chloroform and methylene chloride, ketones, e.g., acetone and methyl ethyl ketone, and aliphatic solvents, e.g., hexane and heptane, as well as mixtures of any of the foregoing solvents.

The com-pounds of Formula II have anticandidal activity as demonstrated by paper disc-agar diffusion assay.

The following examples illustrate the present invention without, however, limiting the same thereto.

Example 1 Sodium nitrile, 2 g., and 2-acetoacetamidopyridne, 1 g., are mixed with 200 ml. of water. The mixture is then adjusted to IpH 3.0 with acetic acid and cooled on ice. After 2 hours at 0 C., the solution is extracted with ethyl acetate and the extract dried (Na2SO4) and concentrated in vacuo. The active material is isolated by chromatography on silica gel using chloroform-methanol (49:1). Sublimation at C. and 0.02 mm. followed by recrystallization from benzene-cyclohexane (4:1) gives 2O mg. of 2-oxo-1(2E)pyridinecarbonitrile, M.P. 100.5-101.5 C. The infrared spectrum in chloroform is shown in FIG. 1. The following absorption bands in reciprocal centimeters are observed:

The ultraviolet spectrum in cyclohexane has maxima or shoulders (sh.) at the following wavelengths (nm.):

sh 219 (e 2100) Sh 292 (4000) 323 (3900) sh 223 (1800) sh 297 (4400) 327 (3500) sh 233 (920) l 309 (5000) 346 (1300) sh 239.5 (300) 314 (5100) Analysis-Calci for C6H4N2O (percent): C, 60.00; H, 3.36; N, 23.33. Found (percent): C, 59.89; H, 3.41; N, 23.14.

The material is very soluble in chloroform and in ethyl acetate and is moderately soluble in benzene. It has little solubility in carbon tetrachloride and in hexane. The nuclear magnetic resonance spectrum in deuterochloroform has complex multiplets at 6.0-6.8 ppm. (2 protons) and at 7.2-7.7 p.p.m. (2 protons) and no other absorption. Activity against Candida albicans SC5314 and Candida tropcals ATCC 13803 is demonstrated by paper disc-agar diffusion assay. f

Example 2 A solution of 2(1 E Ipyridone in one equivalent of 2 N aqueous sodium hydroxide is taken to dryness in vacuo and the residue is recrystallized from ethanol, giving 5 nacreous platelets of the hydrated sodium salt of 20E)- pyridone. A solution of the salt (10.8 g.) in 260 ml. of dimethylformarnide (DMF) is added to a stirred solution of 13.0 g. of cyanogen bromide in 10 ml. of DMF at 0 chloroform at room temperature. The solution is stirred at room temperature for 0.5 hour and then the solvent is removed by distillation. After removal of the solvent, diethylcyanamide is isolated by distillation at 10 torr.

over a period of 1 5 hours. After stirring for an addi 5 2 -pyridone is recovered from the residue by crystallizational 10 minutes at 0, the DMF is removed in vacuo. non' The residue (dark brown) is dissolved as much as possible Examples 4-35 in emol-cfg?? lt'ed .angl thedmtrtedtkentlol dryles Following the procedure of Example 2 but substituting m vacuo fs .131 e 1S en SSO Ve m e y FCC a e 10 for 2(1)pyridone the following substituted Z-pyridones, and the solution 1s passed through a column 0? caf (Bl there is obtained the following correspondingly substituted (300 g) t0 remove the bulk 0f the colored 1mPurme$ 2-oxo-1(2E)pyridinecarbonitriles. The substituents R1, Removal of the solvent gives 7.65 lg. of solid that is then R2, R3 and R4 in both the Starting pydone and the final sublimed at 90-110" C. and 0.02 mm. IRecrystallization pyridinecarbonitrile are as indicated inthe following table:

Ra IRn Ra I B1 Bx I R1 B4 l 0 R4 -0 N/ E EN Example Ri Ra Rs R4 H H H H H H H H H CH H H H CH H H H CHa H H H H H 0H H o! H H C1 H H Br H H Br H H I H H I H H H H H NO2 H O H H CHC- CH=CHCH2 H H H H H H NO2 H CHaCHgO- H H OH H H H 27 Coon H n n 2s CONH, H H H 29 SH H H 3 31.....::;*.:.:... H H CH;

CHaO

00H3 OCE 33 H NO: H H

a4 C1 C1 C1 C1 of the sublimate (5.67 g.) from benzene-cyclohexane (4:1) gives 4.24 g. of pure 2-oxo-1(2I)pyridinecarbo` Examples 36-43 nitrile, M.P. 100.5-10l.5 C. Activity against Candida 70 species is demonstrated as in Example 1.

Example 3 Diethylamine (4.0 g.) is added to a stirred solution of Following the procedure of Example 2 but substituting for 2( 1E) -pyridone the following substituted 2-pyridones, there is obtained the following correspondingly substituted 2-oxo-1(ZJQ-pyridinecarbonitriles. The substituents in 6 g. of 2oxo1(2E)-pyridinecarbonitrile in 60 m1. of 75 the R3 and R4 positions in the starting pyridone (the carbon atom para to the carbon containing the R1 substituent and the carbon atom para to the carbon atom containing the oxo substituent) together form a phenyl ring whose carbons may have substituents R5, R6, R7 and R8. The substituents R1, R2, R5, R6, R7 and R8 in both the 5 starting pyridone and the nal pyridinecarbonitrile are as indicated in Table I.

there is obtained the following correspondingly I'substituted 2oxo1(2g)-pyridinecarbonitriles The substituents in the R1 and R2 positions in the .starting pyridone (the carbon atom para to the nitrogen iatom andthecarbn atom para to the carbon atom containing the R1 substituent) together form a phenyl ring :,yvhose carbops may have substituents R9, R10, Ruandwlm The Isubstituents Ri l R1 l; Rs H Example R1 Rs 37 CHaCONH- H 38 H CHa- H H H H v f 39 (l 0H E H H H CHaC- 40 H (u) H CHaO- H H CHaC- 41 H H H N02 H H 42 Cl H H H H H 43 H H H Br H CHgCHg- Examples 44-58 Following the procedure of Example 2 but substituting R3, R4, Rg, R10, Rll'clndrRlg in the Starting pyl'idOne and the final pyridinecarbom'trile are as indicated in for 2(1 ED-pyridone the following substituted 2-pyridones, 40 Table II.

R1 Rio Example Rl R4 R11 R1:

44 H CH; H H H'. H 45 H H H H E NO:

H H H H H H H E H H H H H H H H H H H H H H H H 0H CHIO- H H n v11 Hv QH .1Min n n n A; Na )in 9 v Examples 59-60 Following the procedure of Example 2 but substituting for ,'2( 1I )pyrid`one the'following substituted 2pyridones, there is obtained'the following correspondingly substituted 2-'oxov1(Zlijfpyridinecarbonitriles. The substituents in theR1 and VR3 positions in the starting pyridone (ther carbonatom para tothe nitrogen atom and the carbon atom*v para tothe carbon atom containing the oxo-substit- Iuent) together form,y a phenyl ring whose carbon atoms :may have substituents R13, R14, R15 and R15. The substituentsR1, R4, R13, R14, R15- and R15 in both the starting pyridone--and the inalpyridinecarbonitrile are as indicated inr Table'IIL l k1R14 v i TABLE, .111

t EamPlves 'G2-8 Eq lowing:[tine procedure of Example 3 but substituting for the diethylaminelin thatl example an equivalent `arr'lount-,ofl the vnucleorphiule listedinColumn I, there is yobtained thejcyanide indicatedin Column II:

TABLE-Continued Example I II 67 nPentylamine CsHu--NH-ON 68 Phenylmagnesium bromide- 69 Ethyl MgBr CzHs-CN 70 Kthn I'nri n C H3 HaC-(l-O-CN 1 5 CH:

71 A'm-mnnin HgN-CN 72 Methyl mercaptan C H1 S -CN 73 Diphenylamino 2 N-CN 74 Morpholine What is claimed is: 1. A compound of the structural formula R I R1 R4 O N EN wherein for each compound of the foregoing structural formula R1, R2, R3 and R1 have the values indicated in the following table:

TABLE-Continued R1 Rz COOH H i v CONHI H H SH E CHzO OH; CH:

Rg R4 H l N02 l C1 Cl C1 C Y 2. A compound of claim 1 having the name 2oxo- References Cited ,y l 1(2g)-pyridinecarbonitrile UNITED STATES PATENTS 3. A process for preparing a compound of claim 1 com- 30 3,668,211 6/1972 Crabtree 260 294 9 prising treating an alkali metal salt of 2(1g)pyridone or Y a substituted derivative thereof with a cyanogen halide. OTHER REFERENCES 4- A PI'OCCSS according to claim 3 wherein the CyaIlO- Roberts et al.: Basic Principlesvof. OrganieQhemiStry, gen halide is cyanogen bromide. 35 vlBenjamin lPublishers, Yp. 806, 19,65,A l; 1

5. A process according to claim 3 wherein the alkali n v f metal salt is obtained by reacting a 2(1 1? I -pyridone with ALAN L' ROTMAN .I t an alkali metal hydride, an alkali metal amide or an or- Y U'S. CLYXRWK J Y n 1k l' .Y y gano a a metalcompound 40 26o-247.2 A, 283 619,281 R, 293,59,-293.69,-294.8 G, 294.9, 295.5 R, 295.5414, 297 Z; Y 7173s, 94; 12A-T248, 258, 263, 266, 267 Y v A l @-1050 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,769, 291 Dated october 3o, 1973 Ihwentorw) William Lawrence Parker et al.

It is certified that error appears in the above-identified patent end that said Letters Patent are hereby corrected as shown below:

, YV g 1 Column 4, line 34, "nitrile" should read nitrite. Column 4, line 58, before "239.5" Vdelete "sh". Column 6, the formulas at the beginning of the table should read:

R3 I R1 R4 O Column 6, example 32, column R3 the formula should read Column 8, in both of the formulas at the beginning of the table,

. should read I c v f R2 Column l0, claim l, the formula should read Rlll I R4 N O Signed and sealed this 23rd dag' of April 197A. i

(SETCTL) Attest:

EEMEE -TQELETGEEESJEQ @o MARSHALL DMN Attestng Officer Commissioner of Patents 

